Project Summary/Abstract: This proposal represents a five-year research career development program focused on the study of longitudinal cognitive outcomes among children and adolescents with HIV in Zambia. The outlined proposal builds on the candidate?s prior research and experience, and will introduce the candidate to new skills that will be shared by the mentorship team led by Dr. Gretchen Birbeck, an expert in neuroepidemiology and clinical trials in resource-limited settings. The proposed training and mentored research will enable the candidate to transition to an independent research career focused on neurologic complications of HIV. Cognitive impairment is common in children with Human Immunodeficiency Virus (HIV) in low-resource settings, affecting up to 50% of perinatally-infected children in Sub-Saharan Africa. In children with HIV receiving Antiretroviral Therapy (ART), opportunistic infections and severe HIV-associated progressive encephalopathy have become less common, but more subtle forms of cognitive impairment have increased in prevalence. The foundation for this proposal is based on research conducted by the candidate as part of the HIV-associated Neurocognitive Disorders in Zambia (HANDZ) study, in which 208 children and adolescents with HIV and 208 HIV-exposed uninfected controls were recruited, and clinical risk factors and biomarkers for cognitive impairment were evaluated. In the HANDZ study, we found that serum markers produced by activated platelets and pro- inflammatory monocytes associated with depression, cerebrovascular disease, and cognitive impairment, suggesting that platelet-monocyte complexes (PMCs) may be key drivers in HIV-associated cognitive impairment. In the proposed project, the population recruited as part of HANDZ will be followed longitudinally for a total of five years, and an additional HIV-unexposed uninfected control group will be recruited. The aims of this proposal include 1) To evaluate whether PMCs and pro-inflammatory monocytes predict depression and cognitive outcomes in ART-treated children and adolescents with HIV in Zambia 2) To assess whether PMCs and pro-inflammatory monocytes are associated with cerebrovascular disease in ART-treated children and adolescents with HIV and 3) To develop a comprehensive predictive model of cognitive change in children with HIV incorporating clinical characteristics, plasma biomarkers, and imaging biomarkers. The short- term goal of this application is to 1) Train the applicant through mentored research 2) Identify a subpopulation of children and adolescents with HIV at high risk of cognitive decline and 3) From clinical profiles, plasma biomarkers and imaging characteristics, identify factors associated with the greatest effect on cognitive outcomes that can be targeted in future intervention studies. The long-term impact will include setting the stage for clinical trials of interventions to prevent or treat HIV-associated neurocognitive disorders in children and adolescents.